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Treatment of neuroblastoma with metaiodobenzylguanidine: results and side effects.

Between April 1984 and December 1985 we treated ten children suffering from neuroblastoma in a total of 25 metaiodobenzylguanidine (MIBG) courses. Five had had a relapse of neuroblastoma stage III or IV, three had never achieved a remission in spite of intensive chemotherapy, and two were treated with an unstable remission. The children were each administered from 1 to 5 courses with a dosage per course of between 1,295 and 9,065 MBq. The sum of the single doses during the whole course of therapy ranged between 3,145 and 21,904 MBq per child. Five of five children suffering from bone pain and fever became free of complaints during the first three treatment days. Six of eight children with manifest tumor at onset of therapy responded well to the treatment: response extended from transitory decrease in elevated catecholamine levels in serum and urine to complete disappearance of large abdominal tumor masses. We also observed a decrease in bone marrow involvement and a stabilization of osteolytic lesions. Seven of these eight children died in spite of a good response from 55 to 350 days after the first MIBG treatment course. The only side effect we witnessed was a reversible bone marrow depression. In three children we combined the MIBG therapy with bone marrow transplantation.

3-Iodobenzylguanidine↗

The diagnosis and staging of neuroblastoma.

Forty-five cases of neuroblastoma were reviewed to assess the value of current diagnostic methods. Urinary catecholamine and 3-methoxy-4-hydroxymandelic acid levels were elevated in only 48% and 60% of cases, respectively. All abdominal or pelvic tumour masses were detected by intravenous urography, ultrasound or computed tomography (CT): CT was the best single investigation but the two less expensive techniques detected most of the tumours. Trephine biopsy was more successful than aspiration in detecting bone marrow metastases. Liver scintigraphy was positive in six of seven cases with hepatic secondaries.

Abdominal Neoplasms↗

Immunocytochemical detection of tumor cells in bone marrow and peripheral blood stem cell collections from patients with ovarian cancer.

High-dose chemotherapy (HDC) followed by autologous hematopoietic reconstitution is an experimental treatment option for patients with epithelial ovarian cancer. However, the incidence of occult ovarian tumor cell involvement in autologous bone marrow (BM) or peripheral blood stem cell (PBSC) autografts has not been widely investigated. We used a highly sensitive immunocytochemical (ICC) procedure that detects occult blood-borne tumor micrometastases. We analyzed 24 BM specimens (15 obtained during therapy and 9 harvest samples) and seven PBSC specimens from 22 patients with ovarian cancer. Overall, ICC analysis detected immunostained tumor cells in 10 of 23 evaluable BM specimens (43%) from 9 of 19 patients (47%). One of 9 (11%) harvest samples contained tumor cells. Only one of the 10 ICC-positive BM specimens had tumor cells detected by routine histopathological analysis. ICC-detectable tumor cells were cleared from the marrow of two patients during chemotherapy. None of the seven PBSC specimens contained tumor cells. We conclude that ovarian cancer micrometastases have the potential to contaminate BM, as is also the case in patients with other epithelial malignancies. In the limited number of specimens analyzed, PBSC harvests appeared to provide a less tumor-contaminated source of hematopoietic stem cells for autologous transplantation.

Antibodies, Monoclonal↗

Hemorrhagic cystitis associated with allogeneic and autologous bone marrow transplantation for malignant neoplasms in adults.

We investigated the occurrence of hemorrhagic cystitis in 30 consecutive adult patients undergoing bone marrow transplantation (BMT) for hematological and non-hematological malignancies. Ten patients with hematological malignancies received allogeneic BMT, and twenty patients, seven with hematological and 13 with non-hematological malignancies, received autologous BMT. All 30 patients received high-dose cyclophosphamide-containing regimens (120 mg/kg in 16, 200 mg/kg in one, 6000 mg/m2 in 13) as preparative therapies. They all received 2-mercaptoethane sulphonate sodium (mesna) combined with hyperhydration 3 liter/day as prophylaxis for hemorrhagic cystitis. Bladder irrigation was not performed. Overall, five patients (16.7%) developed hemorrhagic cystitis; early-onset (within 48 hours of the end of the high dose chemoradiotherapy) hemorrhagic cystitis occurred in one (3.3%; 95% confidence interval, 0.6-16.7%) and late-onset occurred in four (13.3%; 95% confidence interval, 5.3-29.7%). In three of the four late-onset cases, adenovirus was isolated from the urine specimens at the onset of the hemorrhagic cystitis. Among the 13 patients with non-hematological malignancies receiving autologous BMT, one with recurrent breast cancer developed late-onset hemorrhagic cystitis associated with adenovirus type 11. We conclude the prophylactic measure with mesna and hyperhydration to be effective enough to prevent cyclophosphamide-induced hemorrhagic cystitis of early onset. Some BMT recipients, however, even those with non-hematological malignancies undergoing autologous BMT, develop late-onset hemorrhagic cystitis in which adenovirus is considered a principal causative agent.

Adult↗

Therapeutic use of 131I-metaiodobenzylguanidine (MIBG) in neuroblastoma: a phase II study in nine patients.

Effects of high activities of I 131 meta-iodobenzylguanidine (mIBG) were evaluated in nine children with advanced neuroblastoma. All patients had been previously heavily treated and had either primarily refractory disease or resistant relapse. Twenty-two doses of mIBG labeled with 1.3 to 4 GBq (35-108 mCi) of iodine 131 were administered. Three subjective effects, especially relief of pain, and two objective effects were observed. Transient blood pressure increase was observed once and did not recur after prolongation of the infusion time to 6 hours. A major side effect was bone marrow toxicity, essentially marked by thrombopenia, particularly severe in previously bone-marrow-transplanted patients.

3-Iodobenzylguanidine↗

Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review.

BACKGROUND: The central nervous system (CNS) can be a sanctuary site for cancer cells, because the blood-brain barrier impedes penetration of most chemotherapeutic agents. The authors hypothesized that, with improved survival from childhood metastatic neuroblastoma (NB), the incidence of CNS (intraparenchymal and leptomeningeal) spread may increase. They undertook this study to assess the frequency of CNS NB, to analyze risk factors and treatment options, and to review the literature. METHODS: The authors retrospectively analyzed all patients with metastatic NB who were treated on protocols N4, N5, N6, and N7 from 1980 to 1999 at Memorial Sloan-Kettering Cancer Center (MSKCC), during which time there was an increase in the overall survival rate. RESULTS: Two hundred fifty-one patients with Stage 4 NB (Group 251) were studied, of which 127 (Group 127) were newly diagnosed patients who were treated initially at MSKCC. None had CNS NB at the time of diagnosis. Eleven patients developed documented CNS disease; 8 of these 11 recurrences were isolated in the CNS. For Group 127, the overall incidence rate of CNS NB was 6.3%, with an increase in incidence from N4-N5 to N6-N7 of from 1.7% to 11.7%. Seven patients had isolated CNS disease recurrences. Only lumbar punctures (LP) performed near the time of diagnosis in patients with known bone marrow involvement were associated with subsequent development of CNS disease. For the entire group of 251 patients, lumbar puncture at the time of diagnosis and elevated serum lactic dehydrogenase levels were prognostic. Among the larger series reported in the literature, CNS involvement from metastatic lesions was rare at the time of diagnosis and remained an uncommon complication. CONCLUSIONS: The incidence of CNS NB may be increasing. Because it is the sole site of disease recurrence in 64% of patients, the CNS may represent a sanctuary site for NB. CNS NB is associated with diagnostic lumbar punctures in patients with known bone marrow disease, raising the possibility that circulating or epidural microscopic tumor cells may seed the craniospinal axis.

Adrenal Gland Neoplasms↗

Bone marrow immunoscintigraphy for the detection of skeletal metastases in patients with breast cancer.

In this study, we evaluated the efficacy of bone marrow immunoscintigraphy (BMIS) for the detection of skeletal metastases in 23 patients with histologically confirmed breast cancer. All patients underwent whole-body BMIS 3-6 h after the intravenous injection of 0.20-0.33 mg of the intact anti-NCA 95 MAb BW 250/183 labelled with 259-555 MBq 99Tcm and a whole-body 99Tcm-MDP bone scan. In four patients, BMIS SPET of the lumbar spine was also performed. Serum alkaline phosphatase was determined in all patients and the level of human anti-mouse antibody (HAMA) in 16. Final diagnosis was confirmed by radiology and 2 years follow-up. Compared with the 99Tcm-MDP bone scan, BMIS demonstrated better specificity (88% vs 75%) and a better positive predictive value (92% vs 85%). There were no significant differences between BMIS and the bone scan in the detection of skeletal metastases (P > 0.05). In one patient with normal planar BMIS of the lumbar spine, SPET disclosed a metastatic lesion in the bone marrow. The correlation coefficient between BMIS and bone scan and between BMIS and serum alkaline phosphatase was r = 0.688 and r = 0.483 respectively. One patient developed a minor HAMA response after BMIS. Patients with diffuse increased activity of the skull on the bone scan had a significantly higher skull to whole body ratio on BMIS (P < 0.01). Thus BMIS can improve the specificity and positive predictive value of bone scanning in the detection of skeletal metastases, with a low HAMA response. Diffuse increased activity of the skull on bone scans could be explained by bone marrow extension. SPET scanning of the spine may improve the sensitivity of BMIS.

Adult↗

Flow cytometry in the bone marrow staging of mature B-cell neoplasms.

BACKGROUND: Even though flow cytometric (FC) analysis of bone marrow aspirates is often performed in hematolymphoid disorders at diagnosis and during disease monitoring, its role has not been defined during the staging of B-non-Hodgkin's lymphoma (B-NHL) and B-cell lymphoproliferative diseases. The goal of this study was to provide an objective evaluation of how FC might help in the detection of bone marrow involvement by the different types of B-cell malignant neoplasms. METHODS: Fifty-four staging and 156 restaging bone marrow biopsies and bone marrow aspirates, obtained from 185 consecutive patients, were analyzed retrospectively. The results of the morphologic examination and FC were reviewed independently, and their ability to detect bone marrow involvement was compared. RESULTS: FC and morphology agreed in 176 cases (83.8%), i.e., both showed 77 positive cases and 99 negative ones. Discrepant results were obtained in 30 cases (14.2%) in which morphologic examination showed 25 (11.9%) positive cases, whereas FC showed no evidence of disease. FC detected involvement in five cases (2.4%) in the presence of a histologically negative bone marrow biopsy. All morphologically undetermined bone marrow cases (four) were negative by FC. CONCLUSIONS: Neither morphologic examination nor FC alone is adequate for the detection of all cases of B-lymphoid neoplasm bone marrow involvement. FC failed to detect bone marrow involvement in those B-NHL cases having focal paratrabecular infiltration, but proved to be more sensitive than histology in detecting small clonal B-cells in B-NHL, which demonstrated fewer than 5% neoplastic infiltrates. The clinical relevance of minimal disease detected by FC alone needs further evaluation because staging of lymphomas currently is based only on morphologic data.

Biopsy↗

The use of antisera to epithelial membrane antigen in detecting micrometastases in histological sections.

We have investigated, by immunocytochemical means, the value of an antiserum raised to milk-fat-globule membranes in detecting metastatic deposits of breast carcinoma in conventional histological sections of liver, lymph nodes and marrow. The antiseum recognizes a membrane component, which we have called Epithelial Membrane Antigen, and which is confined to but widely distributed in epithelial tissues and tumours derived from them. In the sections examined, a greater extent of tumour infiltration was usually found, largely due to the identification of single malignant cells which normally go unrecognized with conventional stains. The number of positive samples was only increased, however, in sections of marrow aspirates, and the reasons for this are discussed. We suggest that further increases in detection rates could be attained by using the antiserum on cytological smears of marrow or even in cell suspensions.

Antigens, Neoplasm↗